Risk stratification through extensive allergy work‐up in <scp>COVID‐19‐mRNA</scp> vaccine allergic reactions
Authors: Angèle Soria, Marina Labella, Inmaculada Doña, Pascale Nicaise‐Roland, Sylvie Chollet‐Martin, Jean‐Eric Autegarden, Julie Castagna, Claire Le Thai, Luc de Chaisemartin, Maria José Torres, Annick Barbaud
Journal: Allergy (2023)

To the Editor, The mechanisms of allergic reactions to COVID-19-mRNA vaccines have not been elucidated. Polyethylene glycol (PEG) allergies through IgE activation and a complement activation-related pseudoallergy (CARPA) mechanism have been suggested.1, 2 Here, we report the results of allergy work-up and outcomes of subsequent COVID-19 vaccinations in patients with a suspicion of hypersensitivity to COVID-19-mRNA vaccines to determine risk factors for anaphylaxis at the next dose. Between May 2021 and May 2022, 190 patients (180 females (95%), mean age: 51 years old) who were referred to two allergy centers (French and Spanish) for suspicion of allergy to COVID-19-mRNA vaccines were included, with the agreement of the ethics committees. After a detailed analysis of the medical history, immediate, delayed reactions compatible with hypersensitivity and reactions not suggestive of hypersensitivity were reported in 69, 84 and 37 patients, respectively (Figure 1; Table S1). Thirty-one patients with index anaphylaxis (16%) were included, with only three patients who had severe anaphylaxis (Table 1).3 All of the anaphylaxis episodes occurred within one hour after vaccine administration, and the severe episodes occurred in less than 15 min. For all patients, the allergy work-up included skin tests (STs) with the COVID-19-mRNA vaccine and PEGs with molecular weights (MWs) between 400 and 4000; moreover, in the 45/69 patients with immediate reactions, basophil activation tests (BATs) to PEG-2000 MW were performed (Table S4 and Supplement S5). The work-up was positive in nine patients (4.7%): 4/69 patients were positive to PEGs-STs, 1/69 patient was positive to mRNA vaccine-STs and 5/30 patients were positive to PEG2000-BATs (Supplemental S5) (one patient had both positive ST and BAT). One hundred and sixty patients (84%) were revaccinated (122 under antihistamine premedication), 139 patients (87%) had good tolerance, and 30 patients refused further COVID-19 vaccination. In 145 patients, revaccination was performed with the culprit vaccine, which was well tolerated in 126 of the patients, and 15 of the patients had an alternative COVID-19 vaccine (other mRNA vaccine for 12), which was well tolerated in 13 of the patients (Figure 1). Among the 31 patients reporting anaphylaxis, 23 were revaccinated with the culprit vaccine under hospital supervision, with good tolerance in 15 (65%) (Table S6). The eight immediate reactions after revaccination were less severe than the index reaction. Among the five patients with positive PEGs- or vaccine-STs, two tolerated another COVID-19-mRNA vaccine, two another COVID-19 vaccine and one refused further vaccination. Despite a positive PEG2000-BAT test in five patients, two tolerated either the culprit vaccine or another COVID-19 vaccine (Tables S2 and S3). This series strongly argues for revaccinating patients with suspected vaccine allergies. Our results are in accordance with those of Krantz et al.,4 who reported 189 patients with adverse reactions occurring within 4 h after the first dose of the COVID-19-mRNA vaccine. Of the 32 patients with anaphylaxis, 19 received a second dose of COVID-19-mRNA vaccine with good tolerance. Among the 159 patients who received the 2nd dose of vaccine, 32 (20%) had a recurrence of nonsevere manifestations.4 Our results are in accordance with the 2022 ENDA/EAACI recommendations for management of allergies to COVID-19 vaccines,5 but we suggest that the threshold for anaphylaxis episodes appears to be one hour, rather than the timeline recommended by the guidelines. STs with COVID-19-mRNA vaccine and PEG-2000 helps for the pursuit of vaccination. The positive predictive value of the ST and BAT to PEGs and/or COVID-19-mRNA vaccines is unknown, as three patients were reported to have positive STs to PEG-3350 MW and had tolerance of revaccination with an COVID-19-mRNA vaccine.6 The majority of patients suspected of allergy to COVID-19-mRNA vaccines exhibited mild manifestations. Severe anaphylactic reactions appear to be rare; the severity and the occurrence of the reaction within one hour after vaccine are crucial to establish the risk stratification of an allergic reaction to COVID-19-mRNA vaccine. We thank Mrs. Odaliz Duverneuil for her help in recording clinical data and Mrs. Amel Touati, Dr. Laurence Bérard and Pr. Tabassome Simon for their help in the COVALL study. Grants from Région Ile de France and Ministère de la Recherche et de l'Enseignement superieur (APHP210641/N° EUDRACT:2021-003155-42 CRC APHP COVALL Grant). ML is supported by the "Río Hortega" program [CM20/00210] from the Institute of Health "Carlos III" (ISCIII) and ID holds an SAS Stabilization contract (ref B-0001-2017) by Andalusian Regional Ministry Health. Grant from the Agence Nationale de la Recherche (ANR-21-COVR-0020). The Authors have no conflict of interest in relation to this manuscript. Appendix S1: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.